A number of publications are cited herein in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Each of these references is incorporated herein by reference in its entirety into the present disclosure, to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.
Throughout this specification, including the claims which follow, unless the context requires otherwise, the word “comprise,” and variations such as “comprises” and “comprising,” will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a pharmaceutical carrier” includes mixtures of two or more such carriers, and the like.
Ranges are often expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent “about,” it will be understood that the particular value forms another embodiment.
This disclosure includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
Springer et al., 2009, describes certain compounds including, for example, compound AA-018 shown below, which are useful, for example, in the treatment of cancer.

Springer et al., 2009 also describes methods of preparing such compounds. As part of those methods, the 3-oxo-4H-pyrido[2,3-b]pyrazin-8-yl group is formed in a mixture of two regioisomers (the 2-oxo and 3-oxo regioisomers) by a cyclisation reaction of a 2,3-diamino-4-oxy-pyridyl compound with ethyl glyoxylate, as illustrated in the following scheme (drawn from Synthesis 27 therein).

The method used in Synthesis 27 therein is described as: “Using Method D1 with tert-butyl 4-(2,3-diaminopyridin-4-yloxy)-2-fluorophenyl carbamate (3.50 g, 10.5 mmol), tert-butyl 2-fluoro-4-(2-oxo-1,2-dihydropyrido[2,3-b]pyrazin-8-yloxy) phenyl carbamate (2.71 g, 69%) and tert-butyl 2-fluoro-4-(3-oxo-1,2-dihydropyrido[2,3-b]pyrazin-8-yloxy) phenyl carbamate (0.96 g, 25%) were obtained.”
For reference, “Method D1” is described in the context of Synthesis 25 therein as: “tert-butyl 4-(2,3-diaminopyridin-4-yloxy)phenylcarbamate (0.86 g, 2.71 mmol) was dissolved in 15 ml of dry ethanol; 0.8 ml (4 mmol) of a 50% ethyl glyoxylate solution in toluene were added and the solution was stirred overnight at room temperature under Argon atmosphere. The solvent was partially evaporated, and tert-butyl 4-(2-oxo-1,2-dihydropyrido[2,3-b]pyrazin-8-yloxy)phenylcarbamate (0.430 g, 45% yield) is precipitated by addition of acetone (10 ml) and filtered off.”
Such cyclisation methods suffer from low yield. In addition, both regioisomers are formed, and the undesired regioisomer (“2-oxo”) is formed preferentially. Furthermore, the purification of the desired regioisomer (“3-oxo”) away from the undesired regioisomer can be difficult and may require extensive column chromatography.
Reported yields for the reaction are summarised in the following table.
ReportedCompoundYieldCitation21%Springer et al., 2009 (Synthesis 24) (pages 104-105) 25%Springer et al., 2009 (Synthesis 27) (pages 106-107) 15%Springer et al., 2009 (Synthesis 26) (pages 105-106) 7% (1)Zambon et al., 2010 (Compound 7h) (page S8) 24%Murray et al. 2011 (Intermediate D2) (page 44)(1) Note that there is an error in the publication; the reported yield of 240 mg corresponds to a 7% yield, not a 9% yield.
As described herein, the present inventors have determined that the synthetic method can be very greatly improved (e.g., higher yield; preferential formation of desired regioisomer) by employing a different reagent (i.e., glyoxylic acid), especially under certain reaction conditions, including, in particular, a large excess of glyoxylic acid (i.e., a molar excess of at least about 2).
Cyclisation Using Glyoxylic Acid
The use of glyoxylic acid in methanol for the synthesis of the pyridopyrazinone bicyclic system has been reported in a limited number of publications. In each case, the pyridopyrazinone compounds synthesised were either unsubstituted on the pyridyl ring, or substituted with halogen at the 5-position of the pyridyl ring.
Bekerman et al., 1992, describes the reaction of unsubstituted 2,3-daminopyridine with glyoxylic acid and derivatives in a number of solvents. In methanol, the reaction constant for the undesired regioisomer (“2-oxo”) is higher than the reaction constant for the desired regioisomer (“3-oxo”). In chloroform, the ratio is even higher in favour of the undesired regioisomer. In aqueous media, the desired regioisomer is formed preferentially; however, these conditions are not suitable for water insoluble compounds.
Milbank et al., 2011, describes the synthesis of 7-bromopyrido[2,3-b]pyrazin-3(4H)-one from 5-bromopyridine-2,3-diamine and glyoxylic acid in methanol. However, the isomers were obtained as a mixture and were not separated.
Ballell et al., 2008, describes the same synthesis in water, where the undesired 7-bromopyrido[2,3-b]pyrazin-2(1H)-one is obtained as the major isomer in 66% yield. Similarly, the undesired 7-fluoropyrido[2,3-b]pyrazin-2(1H)-one was obtained as the major isomer in 54% yield.
To date, there has been no report of the use of a corresponding method for the synthesis of 4-substituted pyrido[2,3-b]pyrazin-2(1H)-ones. Therefore, the regioselectivity of the cyclisation reaction could not have been predicted with reasonable certainty. Furthermore, the high regioselectivity demonstrated by the inventors and described herein is surprising and unexpected.
Additional publications which describe the use of glyoxylic acid or a glyoxylic acid ester for cyclisation include the following: Abosolo et al., 1990; Bates et al., 1990; Bergman et al., 1996; Clark-Lewis et al., 1957; Cushman et al., 1992; Dettner et al., 1996; Dubey et al., 2001; Leese et al., 1955; Mashelkar et al., 2006; McKillop et al., 1997; Reck et al., 2011; Remli et al., 1989; Rudy et al., 1938; Seki et al., 1995; Sherman et al., 2007; Ziegler et al., 1949.